The expanding HIV-1 pandemic, and the failure of human efficacy trials of T-cell and antibody-based vaccines, highlight the major gaps in knowledge that must be filled in order to pursue rational HIV-1 vaccine design and development. One of the most important knowiedge gaps relates to the precise nature of early virus-host interactions that lead to virus transmission and productive clinical infection. This application is a new HIVRAD proposal by investigators whose recent scientific discoveries relate directly to this priority area of research. These discoveries - the identification of transmitted/founder HIV-1 and SIV genomes (Keele 2008; Keele 2009; Salazar 2009), the identification of genetically-divergent SIVsmm strains in naturallyinfected sooty mangabeys (Apetrei 2005; Apetrei 2007), and the identification of innate mucosal immune responses modulating early virus-host interactions (Estes 2006; Estes 2008; Li 2009) - create a unique and timely opportunity to focus three cutting edge research themes on a high priority HIV/SIV vaccine research problem. The current proposal is comprised of three interrelated projects and two cores led by investigators at the University of Alabama at Birmingham (Shaw and Hahn); the University of Pittsburgh (Apetrei and Pandrea); and NCI-Frederick (Estes, Keele and Lifson). Project #1 is Mucosal transmission and pathogenicity of novel SIVsmm virus strains (Apetrei). Project #2 is Identification, cloning and characterization of transmitted/founder SIVsmm (Hahn). Project #3 is Molecular analysis of the mucosal SIVsmm transmission bottleneck (Shaw). Collectively, the projects will test this hypothesis: Identification, molecular cloning, and in vivo analysis of naturally-occurring mucosally-transmitted strains of SIVsmm corresponding to transmitted/founder viruses will reveal viral-host interactions responsible for selective SIV transmission across rectal, vaginal and cervical mucosa and will provide novel, genetically-divergent, pathogenic virus challenge strains for vaccine testing. A key deliverable of this research to the SIV/HIV vaccine field, in addition to new scientific insights into mucosal transmission, will be 18 molecular clones of transmitted/founder viruses representing three widely divergent SIVsmm genetic lineages for use as potential challenge stocks.